Research on the relationship between the immune system and the nervous system provides evidence of anatomical and physiological pathways through which stress may modulate the immune response. Studies conducted in humans have demonstrated that an increase in psychological stress sustained over time can lead to adverse immunological changes. Therefore, the long-term objective of this study is to define the mechanism(s) by which stress affects the immune response to an infectious agent. In this application, the mechanism(s) by which stress causes immunosuppression and affects health will be examined in an experimental influenza viral infection in an animal model. Infection of mice by influenza virus provides a model of an acute respiratory infection. The specific aims of the program are to assess the effect of restraint stress on the immune response during the effect of restraint stress on the induction of the pituitary-adrenal axis and catecholamines will be investigated during infection to determine the mechanism of immunoregulation by which these hormones (ACTH and corticosterone) and biogenic amines (norepinephrine, epinephrine, and dopamine) affect a virus-specific immune response. Resolution of an influenza viral infection requires the activation of antigen-specific T lymphocytes. CD4+ T lymphocytes possess an antigen receptor complex that binds specific viral antigen which has been processed and presented by antigen-presenting cells in association with class II major histocompatibility complex molecules (MHC). Activation of CD4+ lymphocytes results in the expression of genes coding for lymphokines and is associated with the development of delayed-type hypersensitivity (DTH) responses. Furthermore, lymphokine production by CD4+ lymphocytes is central to the effective generation of antigen-specific cytolytic T lymphocytes (CD8+) and provides helper functions for the production of virus-specific antibodies. Activated T cells are not sessile, they traffick in and out secondary lymphoid tissues and tend to accumulate in sites of inflammation. During the course of an influenza infection, virus- specific T cells accumulate at the site of virus replication (the lung), in the draining lymph nodes (mediastinal) and in the spleen. In previous studies it was shown that restraint stress significantly altered the inflammatory response in the lung, reduced the accumulation of lymphocytes in the lung during infection, and suppressed the IL-2 response by mediastinal and splenic CD4+ T cells stimulated with influenza virus. Thus, the influenza virus model provides a system in which to examine the immunological, endocrinological, and pathological changes associated with stress during a viral infection.